Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase III randomized trial.

BACKGROUND & AIMS: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. METHODS: In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. RESULTS: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV. CONCLUSIONS: Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. IMPACT AND IMPLICATIONS: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96. GOV IDENTIFIER: NCT03852719.

MIC Discrepancies between Parenteral and Oral Anti-Staphylococcal Beta-Lactams among MSSA.

INTRODUCTION: Recent evidence has shown that oral antibiotic therapy is not inferior to IV antibiotic therapy in the treatment of complicated Staphylococcus aureus infections. Therefore, oral antibiotic therapy is now frequently prescribed in clinical practice due to cost benefit, ease of administration, decreased complication rate, and lack of need for IV access. In vitro susceptibility testing for ß-lactam oral antibiotics is not routinely performed as the guidelines provided by the Clinical and Laboratory Standards Institute (CLSI) recommend using oxacillin and cefoxitin as surrogate markers. Hence, oral antibiotic susceptibilities for cephalexin and dicloxacillin are not reported and implied based on oxacillin and cefoxitin. The objective of the current study was to determine whether susceptibilities among S. aureus isolates are predictable when comparing commonly used IV and oral beta-lactams. METHODS: Cefazolin, cephalexin, dicloxacillin, and oxacillin broth microdilution minimum inhibitory concentrations (MICs) were determined for 100 clinical isolates of methicillin-sensitive S. aureus by broth microdilution following CLSI guidelines. RESULTS: Among these isolates, median MICs for cephalexin were eight-fold higher than cefazolin MICs and median MICs for dicloxacillin were four-fold less than oxacillin MICs. Ten percent of more strains studied had a major or very major error in its susceptibility reporting when cephalexin was compared to its surrogate marker oxacillin. DISCUSSIONS/CONCLUSIONS: The variations in MICs observed compounded with the dosing and pharmacokinetic differences of oral versus IV ß-lactam suggests that establishing breakpoints for oral ß-lactam antibiotics is necessary to ensure adequate therapy is selected for the treatment of complex S. aureus infections.

Sofosbuvir-velpatasvir in adults with hepatitis C virus infection and compensated cirrhosis in Japan.

BACKGROUND & PURPOSE: Protease-free regimens for chronic hepatitis C virus (HCV) infection are safe and effective for persons with either compensated or decompensated cirrhosis. We examined the efficacy and safety of sofosbuvir-velpatasvir in participants with HCV and compensated cirrhosis in Japan. METHODS: This was a Phase 3, multi-center, open-label study. At 20 sites, 37 individuals with chronic HCV infection of any genotype and compensated cirrhosis received sofosbuvir-velpatasvir (400 mg/100 mg) daily for 12 weeks. Participants were treatment-naïve or treatment-experienced with interferon-based treatments with or without HCV NS3/4A protease inhibitors. Prior exposure with HCV NS5A or NS5B inhibitors was prohibited. The primary study endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among participants, 62% had HCV genotype 1 infection, and 38% had HCV genotype 2. More than three quarters (29/37, 78%) were HCV treatment naïve. All participants (37/37, 100%) achieved SVR12. Seventeen participants (46%) and three participants (8%) had pretreatment resistance-associated substitutions to HCV NS5A and NS5B nucleoside inhibitors respectively, yet no on-treatment breakthrough or relapse occurred. Sofosbuvir-velpatasvir for 12 weeks treatment was safe and well tolerated. The most commonly reported adverse events were headache (8%, 3/37) and diarrhea (5%, 2/37). One serious adverse event, patella fracture, occurred and was considered not treatment related. No participants discontinued study treatment due to an adverse event. Three participants (8%) had a Grade 3 laboratory abnormality; all were hyperglycemia. CONCLUSION: Sofosbuvir-velpatasvir resulted in high SVR rates and was well tolerated among Japanese patients with HCV and compensated cirrhosis. This single-tablet regimen offers a highly effective, protease-inhibitor free regimen for treating HCV. CLINICALTRIALS: gov Identifier: NCT04112303.

Examining the Combination of Cefixime and Amoxicillin/Clavulanate against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates.

INTRODUCTION: Community-acquired urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli have limited oral therapeutic options and pose significant clinical challenges. The goal of this study was to evaluate the in vitro synergy between CFM and AMC against ESBL E. coli with aims to identify an oral treatment option for UTIs. METHODS: Minimum inhibitory concentrations (MICs) of CFM in the presence of AMC were determined for 46 clinical isolates by placing a CFM Etest on a plate with AMC impregnated in the agar. Isolates with CFM MIC ≤1 µg/mL in the presence of AMC were considered susceptible to the CFM and AMC combination. Five isolates were then selected for further testing using time-kill analysis in the presence of CFM, AMC, and CFM with AMC. Time-kill curves were plotted to determine synergy over 24 h. RESULTS: AMC improved the activity of CFM against ESBL E. coli isolates by 128-fold in the Etest analysis with 85% of tested isolates being susceptible to the combination. A fourfold or greater reduction in CFM MIC was exhibited in 44 of 46 (96%) isolates when in the presence of AMC. Synergy and bactericidal activity between CFM and AMC were exhibited in each of the five isolates tested by time-kill analysis. DISCUSSION/CONCLUSION: This study found that AMC improves the activity of CFM against ESBL E. coli and that this antibiotic combination has potential as an oral therapeutic option to treat ESBL E. coli UTIs.

The role of nonprescription syringe sales in ending the human immunodeficiency virus epidemic.

In 2019, the executive branch of the United States released "Ending the Human Immunodeficiency Virus (HIV) Epidemic: A Plan for America" (EHE). EHE proposes to end the HIV epidemic in the United States by 2030. To do so requires a multifaceted effort from all health care providers addressing every possible avenue of HIV transmission. An important aspect of this mission is to increase access to sterile syringes for people who inject drugs (PWID). For many PWID, access to Syringe Service Programs is limited because of hours, location, and state laws. Pharmacies are able to provide clean syringes in a safe, clean, climate-controlled atmosphere with access to a health professional. Although published research shows pharmacist ambivalence toward the nonprescription sales of syringes, pharmacist involvement in states with established guidance and support from departments of health suggests that pharmacists are interested in this public health effort. However, without proper support from departments of health and access to training on the dignified delivery of services, pharmacies will continue to be an ineffective avenue for prevention of HIV spread through the provision of sterile syringes.

Emergence of Resistance in Klebsiella aerogenes to Piperacillin-Tazobactam and Ceftriaxone.

We examined the effects of piperacillin-tazobactam (TZP) concentration and bacterial inoculum on in vitro killing and the emergence of resistance in Klebsiella aerogenes The MICs for 15 clinical respiratory isolates were determined by broth microdilution for TZP and by Etest for ceftriaxone (CRO) and cefepime (FEP). The presence of resistance in TZP-susceptible isolates (n = 10) was determined by serial passes over increasing concentrations of TZP-containing and CRO-containing agar plates. Isolates with growth on TZP 16/4-µg/ml and CRO 8-µg/ml plates (n = 5) were tested in high-inoculum (HI; 7.0 log10 CFU/ml) and low-inoculum (LI; 5.0 log10 CFU/ml) time-kill studies. Antibiotic concentrations were selected to approximate TZP 3.375 g every 8 h (q8h) via a 4-h prolonged-infusion free peak concentration (40 µg/ml [TZP40]), peak epithelial lining fluid (ELF) concentrations, and average AUC0-24 values for TZP (20 µg/ml [TZP20] and 10 µg/ml [TZP10], respectively), the ELF FEP concentration (14 µg/ml), and the average AUC0-24 CRO concentration (6 µg/ml). For HI, FEP exposure significantly reduced 24-h inocula against all comparators (P ≤ 0.05) with a reduction of 4.93 ± 0.64 log10 CFU/ml. Exposure to TZP40, TZP20, and TZP10 reduced inocula by 0.81 ± 0.43, 0.21 ± 0.18, and 0.05 ± 0.16 log10 CFU/ml, respectively. CRO-exposed isolates demonstrated an increase of 0.42 ± 0.39 log10 CFU/ml compared to the starting inocula, with four of five CRO-exposed isolates demonstrating TZP-nonsusceptibility. At LI after 24 h of exposure to TZP20 and TZP10, the starting inoculum decreased by averages of 2.24 ± 1.98 and 2.91 ± 0.50 log10 CFU/ml, respectively. TZP demonstrated significant inoculum-dependent killing, warranting dose optimization studies.

Adjuvant ß-Lactam Therapy Combined with Vancomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: Does ß-Lactam Class Matter?

We analyzed the impact of vancomycin (VAN) combined with adjuvant ß-lactam therapy (Combo) on persistent (≥5 days) methicillin-resistant Staphylococcus aureus bacteremia versus VAN alone by using pooled data from two previously published observational studies (n = 156). Combo was inversely associated with persistent bacteremia (adjusted odds ratio, 0.460; 95% confidence interval, 0.229 to 0.923). Acute kidney injury was more common with Combo than with VAN (18.9% and 7.6%, respectively; P = 0.062).

Exploring the Role of Piperacillin and Tazobactam in Combination with Vancomycin against Methicillin-Resistant Staphylococcus aureus.

Previous studies have demonstrated synergy between piperacillin (PIP)-tazobactam (TAZ) (TZP) and vancomycin (VAN) against methicillin-resistant Staphylococcus aureus (MRSA). However, it is unknown whether PIP and/or TAZ synergizes with VAN against MRSA. We sought to determine whether PIP and/or TAZ synergizes with VAN against MRSA in vitro. The activity of PIP and/or TAZ with and without VAN (1/2 the minimum inhibitory concentration) was tested against 5 clinical MRSA isolates using a 24-h time-kill methodology. Antibiotic susceptibilities, accessory gene regulator (agr) operon functionality, and US strain type were also determined for the isolates. The combination of VAN and TZP was bactericidal against 3/5 isolates and synergistic against 4/5 isolates tested. Neither PIP nor TAZ alone combined with VAN demonstrated a significant reduction in bacterial growth. The combination of TZP and VAN was less active against the lone isolate with agr dysfunction. In summation, the combination of VAN with both PIP and TAZ was required for synergy against MRSA. This antibiotic combination may not be effective against unique MRSA strain types.

Host-Pathogen-Treatment Triad: Host Factors Matter Most in Methicillin-Resistant Staphylococcus aureus Bacteremia Outcomes.

Previous studies have separately emphasized the importance of host, pathogen, and treatment characteristics in determining short-term or in-hospital mortality rates for patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections. Less is known about the relative importance of these factors and their interactions in determining short-, medium-, and long-term mortality rates. This is an observational cohort study in which data for all patients admitted to the University of New Mexico (UNM) Health Sciences Center (HSC) between July 2002 and August 2013 with MRSA-positive blood cultures were recorded. We collected patients' demographics and treatment data, as well as data on genetic markers of the MRSA isolates. Outcomes of interest were determinants of short-term (within 30 days), medium-term (30 to 90 days), and long-term (>90 days) mortality rates. This study included 273 patients with MRSA bacteremia. Short-, medium-, and long-term mortality rates were 18.7%, 26.4%, and 48%, respectively. Thirty-day mortality rates were influenced by host variables and host-pathogen interaction characteristics. Pitt bacteremia scores, malignancy, and health care exposure contributed to 30- to 90-day mortality rates, while treatment duration of >4 weeks had a protective effect. Age remained a significant risk factor for death at >90 days, while admission leukocytosis was protective. Infection represented the most frequent cause of death for all three time frames; rates varied from 72.6% in the first 30 days and 60% for 30 to 90 days to 35.7% for >90 days (P = 0.003). Host characteristics affect short-, medium-, and long-term mortality rates for MRSA bloodstream infections more than do pathogen genetic markers and treatment factors.

An open-label, pragmatic, randomized controlled clinical trial to evaluate the comparative effectiveness of daptomycin versus vancomycin for the treatment of complicated skin and skin structure infection.

BACKGROUND: Treatment of complicated skin and skin structure infection (cSSSI) places a tremendous burden on the health care system. Understanding relative resource utilization associated with different antimicrobials is important for decision making by patients, health care providers, and payers. METHODS: The authors conducted an open-label, pragmatic, randomized (1:1) clinical study (N = 250) to compare the effectiveness of daptomycin with that of vancomycin for treatment of patients hospitalized with cSSSI caused by suspected or documented methicillin-resistant Staphylococcus aureus infection. The primary study end point was infection-related length of stay (IRLOS). Secondary end points included health care resource utilization, cost, clinical response, and patient-reported outcomes. Patient assessments were performed daily until the end of antibiotic therapy or until hospital discharge, and at 14 days and 30 days after discharge. RESULTS: No difference was found for IRLOS, total LOS, and total inpatient cost between cohorts. Hospital LOS contributed 85.9% to the total hospitalization cost, compared with 6.4% for drug costs. Daptomycin showed a nonsignificant trend toward a higher clinical success rate, compared with vancomycin, at treatment days 2 and 3. In the multivariate analyses, vancomycin was associated with a lower likelihood of day 2 clinical success (odds ratio [OR] = 0.498, 95% confidence interval [CI], 0.249-0.997; P < 0.05). CONCLUSION: This study did not provide conclusive evidence of the superiority of one treatment over the other in terms of clinical, economic, or patient outcomes. The data suggest that physician and patient preference, rather than drug acquisition cost, should be the primary driver of initial antibiotic selection for hospitalized patients with cSSSI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01419184 (Date: August 16, 2011).

Iohexol transmembrane clearance during modeled continuous renal replacement therapy.

BACKGROUND/AIMS: Urea clearance during continuous renal replacement therapy (CRRT) is not representative of middle molecular weight solute clearances. We aimed to characterize iohexol, molecular weight 821 Da, clearance during continuous hemofiltration (CH) and continuous hemodialysis (CHD). METHODS: Using an in vitro model, iohexol sieving coefficients (SC) and saturation coefficients (SA) were determined with the M100 membrane at ultrafiltration/dialysate rates of 1, 2, 3, 4, and 6 l/h. Iohexol transmembrane clearance was calculated using the measured SC and SA. RESULTS: During CH, the value of iohexol SC remained approximately 1 at all ultrafiltration rates studied. In contrast, during CHD iohexol the mean SA was 1.02 ± 0.05 at a dialysate rate 1 l/h and decreased significantly with higher dialysate rates to a mean SA of 0.57 ± 0.12 at a dialysate rate of 6 l/h. CONCLUSIONS: At higher effluent flow rates, CH was more effective in removing iohexol than CHD. CH transmembrane clearance of iohexol appears to approximate the ultrafiltration rate.

Evaluating community pharmacists' HIV testing knowledge: A cross-sectional survey.

OBJECTIVES: To assess community pharmacists' knowledge of human immunodeficiency virus (HIV), antiretroviral therapy, and new in-home oral fluid HIV test. METHODS: A cross-sectional questionnaire administered to pharmacists, student pharmacists, and technicians before an education program at the New Mexico Pharmacists Association 2013 Mid-Winter Meeting in Albuquerque, NM. The main outcome measure was community pharmacists' correct response rate of 75% or more. RESULTS: Overall survey response rate of attendees was 89% (173/194 attendees). Among them 87 participants were community pharmacists; 87% of community pharmacists responded correctly when asked how HIV antiretroviral medications work and 84.3% correctly identified known sources of HIV infection. The 75% predefined adequate knowledge threshold was not met on any HIV screening or in-home HIV test knowledge items. Only 65.1% of community pharmacists correctly identified the minimum number of antiretroviral drugs that should be included in an ideal HIV treatment regimen. The only variable that positively influenced pharmacists' knowledge was age. An inverse relationship between pharmacist age and HIV knowledge was observed among study participants. CONCLUSION: Community pharmacists from urban and rural areas in New Mexico possessed adequate basic HIV knowledge, but did not demonstrate adequate HIV screening or in-home HIV test knowledge. Future educational interventions aimed at improving pharmacist knowledge in this area are warranted.

Assessing appropriateness of antimicrobial therapy: in the eye of the interpreter.

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.

Breaking down the barriers: challenges with development and implementation of an industry-sponsored antimicrobial stewardship data collection and analysis tool.

Partnership between clinicians and the pharmaceutical industry with a focus on antimicrobial stewardship research initiatives is a necessary step toward meeting the shared goals of combating inappropriate antimicrobial use, improving patient outcomes, and minimizing resistance development. Achieving these goals requires outcomes-focused data collection and monitoring tools for antimicrobial stewardship programs (ASP) that consider real-world data about how antimicrobials are used to treat patients. Here we highlight the experiences and challenges associated with the development and implementation of an industry-sponsored electronic antimicrobial stewardship data collection and analysis tool (AS-DCAT). The benefits and risks of the industry-sponsored AS-DCAT from the perspectives of the sponsoring company and participating sites are discussed. Barriers encountered as well as general considerations and recommendations for preventing or overcoming those barriers for future studies and tool development are provided.

Evaluation of vancomycin in combination with piperacillin-tazobactam or oxacillin against clinical methicillin-resistant Staphylococcus aureus Isolates and vancomycin-intermediate S. aureus isolates in vitro.

Vancomycin with piperacillin-tazobactam is used as empirical therapy for critically ill patients. Studies of this combination against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) are limited, but ß-lactams in combination with vancomycin have shown synergistic activity against MRSA and VISA. The goal of this study was to evaluate whether piperacillin-tazobactam and vancomycin were synergistic against MRSA and VISA in vitro. Bloodstream MRSA (n = 20) and VISA (n = 4) strains were selected. In vitro antimicrobial activities of piperacillin-tazobactam and oxacillin were evaluated by disk diffusion, and MICs were determined by Etest using Muller-Hinton agar with and without vancomycin at one-half the MIC. Time-kill studies evaluated 14 MRSA and all 4 VISA isolates using piperacillin-tazobactam at 300/35 mg/liter or oxacillin at 40 mg/liter alone and with vancomycin at one-half the MIC. Mean zones of inhibition for piperacillin-tazobactam and oxacillin increased with vancomycin against MRSA and VISA (P < 0.001 for all), and the MIC90 decreased with vancomycin against MRSA and VISA to values meeting susceptibility criteria for S. aureus (P < 0.001 for both antibiotics against MRSA). In MRSA time-kill studies, the mean 24-h reductions in inoculum for piperacillin-tazobactam, piperacillin-tazobactam with vancomycin, and oxacillin with vancomycin were 3.53, 3.69, and 2.62 log10 CFU/ml, respectively. The mean 24-h reductions in VISA inoculum for piperacillin-tazobactam, piperacillin-tazobactam with vancomycin, and oxacillin with vancomycin were 2.85, 2.93, and 3.45 log10 CFU/ml, respectively. Vancomycin with piperacillin-tazobactam or oxacillin demonstrated synergistic activity against MRSA and VISA. The clinical implications of these combinations against MRSA and VISA should be investigated.

ß-Lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone.

Vancomycin (VAN) is often used to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteremia despite a high incidence of microbiological failure. Recent in vitro analyses of ß-lactams in combination with VAN demonstrated synergistic activity against MRSA. The goal of this study was to examine the impact of combination therapy with VAN and a ß-lactam (Combo) on the microbiological eradication of MRSA bacteremia compared to VAN alone. This was a retrospective cohort study of patients with MRSA bacteremia who received Combo therapy or VAN alone. Microbiological eradication of MRSA, defined as a negative blood culture obtained after initiation of therapy, was used to evaluate the efficacy of each regimen. A total of 80 patients were included: 50 patients in the Combo group and 30 patients in the VAN-alone group. Microbiological eradication was achieved in 48 patients (96%) in the Combo group compared to 24 patients (80%) in the VAN-alone group (P = 0.021). In a multivariable model, the Combo treatment had a higher likelihood of achieving microbiological eradication (adjusted odds ratio, 11.24; 95% confidence interval, 1.7 to 144.3; P = 0.01). In patients with infective endocarditis (n = 22), 11/11 (100%) who received Combo therapy achieved microbiological eradication compared to 9/11 (81.8%) treated with VAN alone, but the difference was not statistically significant (P = 0.20). Patients with MRSA bacteremia who received Combo therapy were more likely to experience microbiological eradication of MRSA than patients who received VAN alone.

Trimethoprim and sulfamethoxazole transmembrane clearance during modeled continuous renal replacement therapy.

BACKGROUND/AIMS: There is limited data regarding trimethoprim (TMP)/sulfamethoxazole (SMX) continuous renal replacement therapy (CRRT) dosing. We aimed to estimate TMP/SMX transmembrane clearance (CLtm) during continuous hemofiltration (CH) and continuous hemodialysis (CD) to guide dosing. METHODS: Using an in vitro model, TMP/SMX sieving coefficients (SC) and saturation coefficients (SA) were determined with high-flux polyarylethersulfone and polyacrylonitrile-sodium methallyl sulfonate copolymer hemodiafilters at ultrafiltration/dialysate rates of 1, 2, 3, and 6 l/h. TMP/SMX CLtm was calculated using measured SC and SA. TMP/SMX CRRT doses were modeled using CLtm and published TMP/SMX pharmacokinetic parameters. RESULTS: TMP SC/SA during CH/CD were significantly higher than SMX SC/SA. During modeling, TMP 10 mg/kg/day and its corresponding SMX dose, 50 mg/kg/day, resulted in steady state TMP/SMX peak concentrations associated with efficacy against Pneumocystis jirovecii. CONCLUSIONS: CRRT resulted in greater TMP CLtm than SMX. TMP 10 mg/kg/day divided q12h may be an appropriate initial dose to consider in patients undergoing CRRT.

Efficacy and Safety of Sofosbuvir/Velpatasvir Plus Ribavirin in Patients with Hepatitis C Virus-Related Decompensated Cirrhosis.

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child-Turcotte-Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3-4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.

Site of infection rather than vancomycin MIC predicts vancomycin treatment failure in methicillin-resistant Staphylococcus aureus bacteraemia.

BACKGROUND: Therapeutic use of vancomycin is characterized by decreased susceptibilities and increasing reports of clinical failures. Few studies have examined the clinical outcomes of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia treated with vancomycin. The primary objective was to compare clinical outcomes of patients with MRSA bacteraemia treated according to standard of care practices. METHODS: Patients were included if: (i) admitted to University of New Mexico Hospital between 2002 and 2009; (ii) ≥18 years of age; (iii) had one blood culture positive for MRSA; and (iv) received vancomycin. Clinical outcomes were defined as cure, failure (relapse of infection 30 days after completion of therapy, death or change in therapy) or unevaluable. Patient demographics, source of bacteraemia, treatment regimen, and microbiological characteristics were determined. RESULTS: Two hundred patients with MRSA bacteraemia were included. Sixty-one patients were unevaluable, leaving 139 patients for the final analysis. Seventy-two (51.8%) patients were cured and 67 (48.2%) experienced vancomycin failure. Vancomycin MIC(90) was 2 mg/L for both groups by Etest. Patients with endocarditis (P = 0.02) or pneumonia (P = 0.02) were more likely to fail therapy. Panton-Valentine leucocidin, loss of agr functionality and strain type were not predictors of outcomes in this study. CONCLUSIONS: High failure rates were observed in patients with MRSA bacteraemia treated with vancomycin, despite high vancomycin troughs and low rates of nephrotoxicity. Predictors of vancomycin failure included endocarditis and pneumonia. In these situations, vancomycin provides suboptimal therapy.